Accompanying the rapid progression to an elderly society in recent years, the number of patients with geriatric diseases, and particularly those with bone diseases, is continuing to increase. In particular, osteoporosis, which is prevalent among women and especially postmenopausal women, is becoming a serious problem. Since accelerated bone resorption brought about by a loss of hormonal balance and aging phenomena in postmenopausal women is intimately related to the onset and progression of bone disease, bone resorption inhibitors have been used during the course of ordinary drug therapy for osteoporosis. However, drugs currently in use that demonstrate bone resorption inhibitory action, such as calcitonin preparations, estrogen preparations, vitamin K preparations and bisphosphonate preparations, have problems in terms of their therapeutic effects, rapid-acting, adverse side effects and patient compliance, thus desiring the development of a bone resorption inhibitor capable of being used as a more effective drug for the treatment or prevention of osteoporosis.
In the living body, bone calcium concentrations and blood calcium concentrations are in a state of equilibrium, and calcium is constantly migrating between the bone and blood. This migration of calcium is governed by dynamic shifts between bone formation and bone resorption. In the process of bone resorption, bone resorption is known to be accelerated as a result of activated osteoclasts eluting bone inorganic substances such as calcium simultaneous to cysteine proteases secreted from osteoclasts decomposing bone organic substances such as collagen. Cysteine proteases such as cathepsin B, cathepsin H, cathepsin L and cathepsin S are present in osteoclast lysosomes, and osteoclast-localized human cathepsin K was isolated in 1995, which was demonstrated to be expressed in osteoclasts in larger amounts than other cathepsins (Biochem. Biophys. Res. Commun., 206, 89 (1995); J. Biol. Chem., 271, 12511 (1996)). Moreover, the cathepsin K gene was demonstrated to mutate in patients with dwarfism presenting with bone resorption abnormalities (Science, 273, 1236 (1997)).
In this manner, attention has been focused on cathepsin K as the main cysteine protease involved in bone resorption, and considerable expectations are being placed on cathepsin K inhibitors as inhibitors of bone resorption. Previously reported examples of compounds having cathepsin K inhibitory action include aldehyde derivatives, epoxy succinic acid derivatives (J. Biol. Chem., 271, p. 2126 (1996); Biol. Pharm. Bull., 19, p. 1026 (1996)) and vinylsulfonic acid derivatives (Nature Structural Biology, 4, p. 105 (1997); J. Med. Chem., 38, p. 3139 (1995)), and these derivatives have low selectivity and are known to strongly inhibit other cysteine proteases in addition to cathepsin K (J. Enzyme Inhibition, 3, p. 13 (1989); Biochem. Biophys. Res. Commun., 153, p. 1201 (1988); J. Biochem., 87, p. 39 (1980); J. Biochem., 88, p. 805 (1980)).
Moreover, accompanying the growing interest in cathepsin K as described above, research has also been actively conducted in the area of X-ray crystal analyses of cathepsin K and inhibitors (Nature Structural Biology, 4, p. 105 (1997); Nature Structural Biology, 4, p. 109 (1997)), and compounds are known that has a selective inhibitory action on cathepsin K (Proc. Natl. Acad. Sci. USA, 94, 142, p. 49 (1997); WO9801133; J. Am. Chem. Soc., 120, 9, p. 114 (1998); J. Med. Chem., 41, p. 3563 (1988); Japanese Unexamined Patent Publication No. 2000-204071; Bioorg. Med. Chem., 14, p. 4333 (2004); Bioorg. Med. Chem., 14, p. 4897 (2004)). In addition, WO971677 identifies the catalyst active site of cathepsin K and discloses a method for inhibiting cathepsin K using a compound that interacts with this active site.
Moreover, although not containing descriptions of inhibition of cathepsin K, Japanese Unexamined Patent Publication Nos. Hei 2-256654 and Hei 2-268145 disclose various types of aldehyde derivatives as protease inhibitors.                [Non-patent document 1] Proc. Natl. Acad. Sci. USA., 94, 142, p. 49 (1997)        [Non-patent document 2] J. Am. Chem. Soc., 120. 9. p. 114 (1998)        [Non-patent document 3] J. Med. Chem., 41, p. 3563 (1998)        [Non-patent document 4] Bioorg. Med. Chem., 14, p. 4333 (2004)        [Non-patent document 5] Bioorg. Med. Chem., 14, p. 4897 (2004))        [Patent document 1] WO9801133        [Patent document 2] WO971677        [Patent document 3] Japanese Unexamined Patent Publication No. 2000-204071        [Patent document 4] Japanese Unexamined Patent Publication No. Hei 2-256654        [Patent document 5] Japanese Unexamined Patent Publication No. Hei 2-268145        